Total synthesis of (-)-cleistenolide

Article abstract of DOI:10.1016/j.tetlet.2011.01.124

The total synthesis of (-)-cleistenolide, a novel natural product recently isolated from the annonaceae species cleistochlamys kirkii oliver, is described. The synthesis proceeds starting from easily accessible d-manitol using a selective benzoylation, a

Full text of DOI:10.1016/j.tetlet.2011.01.124

Tetrahedron Letters 52 (2011) 2443–2445
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Tetrahedron Letters
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Total synthesis of (ꢀ)-cleistenolide
⇑
Palakuri Ramesh, H. M. Meshram
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of (ꢀ)-cleistenolide, a novel natural product recently isolated from the annonaceae
Received 16 October 2010
Revised 24 January 2011
Accepted 27 January 2011
Available online 1 February 2011
species cleistochlamys kirkii oliver, is described. The synthesis proceeds starting from easily accessible
D-manitol using a selective benzoylation, a selective acetonide deprotection, silylprotection and ring-
closing metathesis reaction.
Ó 2011 Elsevier Ltd. All rights reserved.
Naturally isolated 6-substituted-
a
,b-unsaturated-d-lactones
chiral template
deprotection of acetonide, and monobenzoylation (Scheme 1).
The present synthesis commences (Scheme 2) from -(+)-
D
-manitol
6
through the regioselective
gained great attention of researchers due to their cytotoxic and
anti-tumor properties.1 In addition they inhibit HIV protease,2 in-
duce apoptosis,3,4 and have proven to be anti-leukemic,5 along
with having many other relevant pharmacological properties.6
Synargentolide A,7 spicegerolide,8 hyptolide,9 synrotolide,10 and
anamarine11 isolated from syncolostemon and hyptis species are
D
mannitol. The diol 7 is readily accessible from tri-O-isopropyli-
dene-
D
-(+)-manitol,18 with the terminal acetonides acting as
O
examples of
a,b-unsaturated-d-lactones. Due to their pharmaco-
OBz
logical properties, these molecules became the interesting syn-
thetic goals.
O
O
AcO
OAc
O
Cleistochlamys kirkii oliver is an annonaceae species occurring
in Tanzania and Mozambique.12 Extracts of this plant are used in
traditional medicine as a remedy for the treatment of wound
infections, rheumatism, and tuberculosis.13 Recently, Nkunya co-
workers14 investigated the chemical composition of organic
extracts from fruits, leaves, stem and root barks of C. kirkii oliver
and discovered two novel plant constituents, which were named
cleistenolide (1) and cleistodienol (2) (Fig. 1).14 cleistenolide is
known to possess antibacterial activity against staphylococcus
aureus and bacillus anthracis, as well as antifungal activity against
Candida albicans.
OAc OAc
OH
(-)-Cleistenolide
(-)-Cleistodienol
1
2
Figure 1. Chemical structures of cleistenolide (1) and cleistodienol (2).
O
O
O
O
O
Recently, the first total synthesis of cleistenolide was published
by Schmidt et al.15 in overall 18% yield, by applying a ring-closing
metathesis (RCM) protocol to prepare the key building block, an
O
OAc OAc
OBz
OTBS OTBDPS
a
,b-unsaturated lactone. Very recently synthesis of cleistenolide
1
was reported by Cai et al. from the
a
,b-unsaturated acid through
3
(-)-Cleistenolide
an intramolecular Yamaguchi esterification.16
Herein, we report the total synthesis of cleistenolide (1), start-
ing from an enantiomerically pure D-manitol. Our synthesis con-
firms the absolute configuration assigned (ꢀ)-cleistenolide. As
depicted in the retro synthetic analysis of the (ꢀ)-cleistenolide
the crucial dihydropyran-2-one was prepared from ring-closing
metathesis (RCM). Compound 4 would be prepared from benzoy-
lated diacetonide 5. Precursor 5 would be constructed from natural
O
OBz
OTBDPS
5
O
O
O
OBz
D(+)-Manitol
OTBDPS
O
O
6
4
⇑
Corresponding author. Tel.: +91 40 27160123 2642; fax: +91 40 27160512.
E-mail address: hmmeshram@yahoo.com (H.M. Meshram).
Scheme 1. Retrosynthesis of (ꢀ)-cleistenolide.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.124

2444
P. Ramesh, H. M. Meshram / Tetrahedron Letters 52 (2011) 2443–2445
O
O
O
O
Ref-18
a
OH
OBz
D(+)-Manitol
OH
OH
O
O
O
O
6
7
5
O
O
O
OBz
OBz
O
b
c
d
OTBDPS
OTBDPS
OH
O
OH
O
9
8
OH
OH
O
OBz
O
f
e
OBz
OBz
OTBS
OTBDPS
OH OTBDPS
OTBDPS
10
4
11
O
O
O
h
i
g
O
1
OBz
OBz
OTBS OTBDPS
OTBS OTBDPS
3
12
Scheme 2. Reagents and conditions: (a) Pyridine, benzoyl chloride, DMAP, CH2Cl2, ꢀ78–20 °C, 4 h, 83%; (b) TBDPS–Cl, imidazole, CH2Cl2, 0 °C to rt, 86%; (c) CuCl2ꢁ2H2O,
CH3CN, 0 °C, 45 min, 99% (with recovered starting material); (d) PPh3-imidazole-iodine, toluene, 110 °C, 4 h, 84%; (e) PPTS (cat)/MeOH, rt, 86% (or) CuCl2ꢁ2H2O, CH3CN, rt,
20 h, 84%; (f) TBS–OTf (1 equiv), 2,6-lutidine, CH2Cl2, ꢀ78 °C, 85%; (g) acryloyl chloride, DIPEA, CH2Cl2, 0 °C to rt, 81%; (h) 5 mol % Grubb’s 2nd generation catalyst, toluene,
110 °C, 68%; (i) TBAF, THF then Ac2O, 62%.
surrogates for the generation of olefin. The formation of the termi-
nal diol 9 (Scheme 2) from the diacetonide 8 was achieved by the
slight modification of a literature method.18,19
dine, DCM, ꢀ78 °C selectively gave allylic silylether 11, in 85%
yield. Esterification of 11 with acryloyl chloride led to the forma-
tion of 3 in 81% yield. To avoid isomerization of the double bond
by prolonged exposure to the reaction conditions, the reaction
was arrested before complete disappearance of the starting mate-
rial. Ring-closing metathesis of 3 proceeded well with 5 mol % of
Grubbs catalyst. In dilute reaction conditions, the six-membered
ring d-lactone 12 was isolated in 68% yield (Scheme 2).17,20b Com-
pletion of the synthesis required desilylation of 12 and acetylation
of the two secondary alcohols. This was most conveniently
achieved as a one-flask reaction in THF by the addition of TBAF
and subsequent addition of acetic anhydride. Notably, the desilyla-
tion/double acetylation proceeds in the absence of base and with-
out any migration of the benzoyl group. Thus, analytically pure
(ꢀ)-cleistenolide (1) was obtained as a single regio and stereoiso-
mer in a yield of 62%. The physical and spectral data22 of synthes-
ised sample (ꢀ)-cleistenolide 1 were identical to those reported in
the literature.14,16 Our results, as well as Schmidt’s report,15 sup-
port the absolute configuration assigned to natural product as
(ꢀ)-cleistenolide.
Monobenzoylation of diol 7 by using benzoyl chloride and
DMAP in pyridine gave 5 in good yield.19 The hydroxy group of
compound 5 was protected with TBDPS–Cl to give silyl ether 8
with 86% yields. The diacetonide 8 underwent selective hydrolysis
of the terminal acetonide using an equivalent amount of
CuCl2ꢁ2H2O at 0 °C to generate the diol 9 in quantitative yield.20
Pb(OAc)4-cleavage of 9 followed by Wittig reaction provided the
terminal olefin 4 in poor yield along with an unidentified mixture
of products. However, it was smoothly converted 4 by the reaction
with Ph3P-imidazole-iodine in toluene and gave 84% yield.21 Thus,
acetonide cleavage of 4 by PPTS/MeOH (or) CuCl2ꢁ2H2O at room
temperature produced the diol 10 (Scheme 2).19
NMes
MesN
Cl
Ru
Cl
Ph
In summary, we have achieved the total syntheses of (ꢀ)-
cleistenolide from a common precursor simply by changing the
sequence of carbinol protection and thus allowing the formation
of d-lactone. Key features of present route to (ꢀ)-cleistenolide
are the efficient utilization of the C2-symmetry of the starting
PCy3
2
nd generation Grubb's catalyst
material (D-(+)-mannitol), a selective benzoylation, a selective
acetonide deprotection, selective silyl protection and a ring-closing
metathesis reaction.
The key building block 10 is thus synthesized in a facile manner
from -(+)-mannitol in a combined 44% overall yield. The reaction
of compound 10 on treatment with 1 equiv. of TBS–OTf, 2,6-luti-
D

P. Ramesh, H. M. Meshram / Tetrahedron Letters 52 (2011) 2443–2445
2445
1.39 (s, 3H), 3.86 (dd, 1H, J = 4.53, 3.39 Hz), 4.15 (dd, 1H, J = 6.79, 3.23 Hz), 4.22
(dd, 1H, J = 6.04, 5.66 Hz), 4.35 (dd, 1H, J = 7.93, 3.77 Hz), 4.45 (t, 1H,
J = 7.36 Hz), 5.10 (d, 1H, J = 10.38 Hz), 5.30 (d, 1H, J = 17.18 Hz), 5.65 (ddd,
1H, J = 16.9, 10.57, 6.79 Hz), 7.30–7.50 (m, 8H), 7.62–7.78 (m, 7H); 13C NMR
(75 MHz, CDCl3): d 19.2, 26.4, 26.6, 66.2, 69.8, 78.3, 79.5, 111.5, 119.2, 128.6,
129.4, 129.6, 130.0, 130.2, 134.2, 134.6, 165.9; IR (KBr): 3068, 2929, 2857,
1592, 1428, 1260, 1108 cmꢀ1; ESI-MS: m/z 553 [M++Na]; ESI-HRMS: m/z calcd
for C32H38O5SiNa: 553.2386, found: 553.2382.
Acknowledgments
P.R. thanks CSIR for the award of a fellowship and to Dr. J. S.
Yadav, Director IICT, for his support and encouragement.
References and notes
(2R,3S,4R)-2-(tert-Butyldiphenylsilyloxy)-3,4-dihydroxyhex-5-enyl benzoate (10):
½
a 2D5
ꢂ
ꢀ4.24 (c 0.96, CHCl3); 1H NMR (300 MHz, CDCl3): d 1.05 (s, 9H), 2.22 (s,
1. Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985, 24, 94.
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Lovdahl, M.; Tait, B. D.; Wise, E.; Holler, T.; Hupe, D.; Nouhan, C.; Urumov, A.;
Zeikus, G.; Zeikus, E.; Lunney, E. A.; Pavlovsky, A.; Gracheck, S. J.; Saunders, J.
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4. For further literature related to this important biological property, see, for
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1H), 2.65 (s, 1H), 3.58 (ddd, 1H, J = 8.80, 5.62, 2.80 Hz), 4.12 (dd, 1H, J = 9.44,
3.68 Hz), 4.32 (dd, 1H, J = 9.06, 3.02 Hz), 4.42 (dd, 2H, J = 7.36, 4.53 Hz), 5.18 (d,
1H, J = 10.57 Hz), 5.35 (d, 1H, J = 17.18 Hz), 5.80 (ddd, 1H, J = 16.9, 11.57,
6.42 Hz), 7.20–7.40 (m, 8H), 7.50 (t, 1H, J = 7.55 Hz), 7.70 (d, 4H, J = 6.61 Hz),
7.83 (d, 2H, J = 7.17 Hz); 13C NMR (75 MHz, CDCl3): d 19.5, 26.7, 66.2, 71.4, 71.6,
78.8, 115.6, 128.4, 129.5, 130.0, 130.8, 133.4, 134.0, 138.6, 165.8; IR (KBr):
3068, 2929, 2857, 1592, 1428, 1260, 1108 cmꢀ1; ESI-MS: m/z 513 [M++Na];
ESI-HRMS: m/z calcd for C29H34O5SiNa: 513.2073, found: 513.2069.
(2R,3S,4R)-4-(tert-Butyldimethylsilyloxy)-2-(tert-butyldiphenylsilyloxy)-3-hydro-
xyhex-5-enyl benzoate (11): ½a D25
ꢂ
+26.4 (c 2.0, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.18 (s, 6H), 1.03 (s, 9H), 1.20 (s, 9H), 2.75 (d, 1H, J = 4.91 Hz), 3.68
(dd, 1H, J = 4.91, 4.70 Hz), 4.20 (dd, 1H, J = 6.40, 3.20 Hz), 4.45 (dd, 2H, J = 11.52,
5.09 Hz), 4.60 (dd, 1H, J = 9.25, 2.62 Hz), 5.20 (d, 1H, J = 10.57 Hz), 5.35 (d, 1H,
J = 17.34 Hz), 5.80 (ddd, 1H, J = 17.56, 9.63, 7.36 Hz), 7.40–7.60 (m, 9H), 7.70 (t,
1H, J = 7.55 Hz), 7.82–7.95 (m, 5H); 13C NMR (75 MHz, CDCl3): d ꢀ5.3, ꢀ4.9,
18.6, 19.4, 25.9, 26.6, 66.2, 71.5, 71.9, 79.8, 115.7, 128.6, 129.4, 129.9, 130.08,
130.1, 134.0, 137.4, 165.9; IR (KBr): 3442, 2935, 2930, 1728, 1518, 1418, 1398,
1246, 1156, 836 cmꢀ1; ESI-MS: m/z 627 [M++Na]; ESI-HRMS: m/z calcd for
5. Kikuchi, H.; Sasaki, K.; Sekiya, J.; Maeda, Y.; Amagai, A.; Kubohara, Y.; Ohsima,
Y. Bioorg. Med. Chem. 2004, 12, 3203.
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Brankiewicz, A. J.; Steinman, C. E.; Smitka, T. A.; French, J. C. J. Antibiot. 1983, 36,
1601; (b) Nagashima, H.; Nakamura, K.; Goto, T. Biochem. Biophys. Res. Commun.
2001, 287, 829; (c) Raoelison, G. E.; Terreaux, C.; Queiroz, E. F.; Zsila, F.;
Simonyi, M.; Antus, S.; Randriantsoa, A.; Hostettmann, K. Helv. Chim. Acta 2001,
84, 3470; (d) Lewy, D. S.; Gauss, C. M.; Soenen, D. R.; Boger, D. L. Curr. Med.
Chem. 2002, 9, 2005; (e) Larsen, A. K.; Escargueil, A. E.; Skladanowski, A.
Pharmacol. Ther. 2003, 99, 167; (f) Richetti, A.; Cavallaro, A.; Ainis, T.; Fimiani, V.
Immunopharmacol. Immunotoxicol. 2003, 25, 441; (g) Koizumi, F.; Ishiguro, H.;
Ando, K.; Kondo, H.; Yoshida, M.; Matsuda, Y.; Nakanishi, S. J. Antibiot. 2003, 56,
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7. Collett, L. A.; Davies, C. M. T.; Rivett, D. E. A. Phytochemistry 1998, 48, 651.
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1987, 41B, 599.
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Perales, A. Tetrahedron Lett. 1979, 20, 3583.
12. Nkunya, M. H. H. Pure Appl. Chem. 2005, 77, 1943.
13. Verzar, R.; Petri, G. J. Ethnopharm. 1987, 19, 67.
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Moulton, B.; Luisi, B. S. Nat. Prod. Commun. 2007, 2, 737.
15. Schmidt, B.; Kunz, O.; Biernat, A. J. Org. Chem. 2010, 75, 2389.
16. Chao, C.; Jun, L.; Yuguo, D.; Robert, J. L. J. Org. Chem. 2010, 75, 5754.
17. Feurstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H. J.; Nolan, S. P. J. Org. Chem.
2000, 65, 220; (b) Samojlowicz, C.; Bieniek, M.; Zarecki, A.; Kadyrov, R.; Grela,
K. Chem. Commun. 2008, 6282; (c) Rost, D.; Porta, M.; Gessler, S.; Blechert, S.
Tetrahedron Lett. 2008, 49, 5968.
C
35H48O5Si2Na: 627.2432, found: 627.2435.
(2R,3S,4R)-3-(Acryloyloxy)-4-(tert-butyldimethylsilyloxy)-2-(tertbutyldiphenylsil-
yloxy)hex-5-enyl benzoate (3): ½a D25
ꢂ
+56.5 (c 1.50, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.2 (s, 6H), 1.10 (s, 9H), 1.23 (s, 9H), 4.53 (dd, 1H, J = 7.55, 3.77 Hz),
4.62 (ddd, 2H, J = 11.33, 6.79, 4.53 Hz), 4.81 (dd, 1H, J = 8.30, 3.77 Hz), 5.43 (d,
1H, J = 9.80 Hz), 5.48 (dd, 1H, J = 6.04, 3.02 Hz), 5.58 (dd, 1H, J = 17.34, 3.77 Hz),
5.90 (ddd, 1H, J = 17.34, 9.82, 6.70 Hz), 6.20 (dd, 1H, J = 9.06, 3.02 Hz), 6.45 (dd,
1H, J = 10.57, 6.70 Hz), 6.75 (dd, 1H, J = 16.60, 3.02 Hz), 7.40–7.50 (m, 8H), 7.60
(t, 2H, J = 7.55 Hz), 7.70 (t, 2H, J = 7.55 Hz), 7.85 (m, 3H); 13C NMR (75 MHz,
CDCl3): d ꢀ4.7, ꢀ5.2, 18.2, 19.5, 25.7, 26.8, 65.7, 69.0, 72.9, 73.3, 117.6, 127.8,
128.3, 129.6, 129.7, 129.8, 130.0, 131.9, 133.2, 134.1, 135.3, 164.9, 166.5; IR
(KBr): 2949, 2895, 2854, 1727, 1535, 1423, 1240, 1198, 1154 cmꢀ1; ESI-MS: m/
z 681 [M++Na]; ESI-HRMS: m/z calcd for C38H50O6Si2Na: 681.3043, found:
681.3047.
(R)-2-((2S,3R)-3-(tert-Butyldimethylsilyloxy)-6-oxo-3,6-dihydro-2H-pyran-2-yl)-
2-(tert-butyldiphenylsilyloxy)ethyl benzoate (12): ½a D25
ꢂ
ꢀ156 (c 0.5, CHCl3); 1H
NMR (300 MHz, CDCl3): d 0.2 (s, 6H), 1.10 (s, 9H), 1.23 (s, 9H), 4.26 (dd, 1H,
J = 9.77, 2.32 Hz), 4.29 (m, 1H), 4.47 (dd, 1H, J = 5.86, 2.22 Hz), 4.54 (dd, 1H,
J = 12.56, 4.57 Hz), 4.86 (dd, 1H, J = 12.34, 2.32 Hz), 6.10 (d, 1H, J = 10.57 Hz),
6.93 (dd, 1H, J = 9.77, 5.80 Hz), 7.38–7.53 (m, 8H), 7.62 (t, 2H, J = 7.48 Hz), 7.73
(t, 1H, J = 7.48 Hz), 7.83–7.88 (m, 4H); 13C NMR (75 MHz, CDCl3): d ꢀ5.2, ꢀ4.6,
18.0, 19.5, 25.6, 60.0, 66.0, 67.8, 80.0, 122.5, 128.4, 129.4, 129.6, 129.8, 133.3,
144.4, 162.8, 166.9; IR (KBr): 2939, 2855, 1717, 1505, 1423, 1248, 1148,
1054 cmꢀ1; ESI-MS: m/z 631 [M++H]]; ESI-HRMS: m/z calcd for C36H47O6Si2:
631.2906, found: 631.2909.
(ꢀ)-Cleistenolide (1): mp 130–133 °C;
½
a 2D5
ꢂ
ꢀ118 (c 0.5, CHCl3); 1H NMR
(300 MHz, CDCl3) d 2.03 (s, 3H), 2.09 (s, 3H), 4.52 (dd, 1H, J = 12.51, 4.40 Hz),
4.80 (dd, 1H, J = 9.60, 2.62 Hz), 4.93 (dd, 1H, J = 12.51, 2.22 Hz), 5.43 (dd, 1H,
J = 6.02, 2.50 Hz), 5.51 (ddd, 1H, J = 9.50, 4.42, 2.32 Hz), 6.29 (d, 1H, J = 9.60 Hz),
7.00 (dd, 1H, J = 9.60, 6.10 Hz), 7.45 (t, 2H, J = 7.65 Hz), 7.57 (t, 1H, J = 7.42 Hz),
8.01 (d, 2H, J = 7.65 Hz); 13C NMR (75 MHz, CDCl3): d 20.5, 20.7, 59.7, 62.0, 67.7,
75.4, 125.3, 128.5, 129.6, 129.7, 129.7, 133.2, 139.7, 161.0, 166.0, 169.5, 169.9;
IR (KBr): 2954, 1723, 1456, 1367, 1218, 1107, 1070; ESI-MS: m/z 385 [M++Na];
ESI-HRMS: m/z calcd for C18H18O8Na: 385.0894, found: 385.0897.
18. Wiggins, L. F. J. Chem. Soc. 1946, 13.
19. Chandrasekhar, M.; Kusum, L. C.; Singh, V. K. J. Org. Chem. 2003, 68, 4039.
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1998, 39, 3091; (b) Yadav, V. K.; Agrawal, D. Chem. Commun. 2007, 5232.
21. Garegg, P. J.; Samuelsson, B. Synthesis 1979, 469.
22. Spectral data for selected compounds: (R)-2-(tert-butyldiphenylsilyloxy)-2-
((4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)ethylbenzoate
(4):
½ ꢂ
a 2D5
ꢀ2.46 (c 1.4, CHCl3); 1H NMR (300 MHz, CDCl3): d 1.05 (s, 9H), 1.36 (s, 3H),